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Jagroop Singh Saran,1 Amie L Hoefnagel,1 Kristin A Skinner,2 Changyong Feng,3 Daryl Irving Smith1 1Acute Pain Service, Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 2Department of Surgical Oncology, University of Rochester School of Medicine and Dentistry, University of Rochester Medical Center, 3Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA Background: The role of thoracic paravertebral blockade (TPVB) in decreasing opioid requirements in breast cancer surgery is well documented, and there is mounting evidence that this may improve survival and reduce the rate of malignancy recurrence following cancer-related mastectomy. We compared the two techniques currently in use at our institution, the anatomic landmark-guided (ALG) multilevel versus an ultrasound-guided (USG) single injection, to determine an optimal technique.Methods: We retrospectively reviewed records of patients who received TPVB from January 2013 to December 2014. Perioperative opioid use, post anesthesia care unit (PACU) pain scores and length of stay, block performance, and complications were compared between the two groups.Results: We found no statistical difference between the two approaches in the studied outcomes. We did find that the number of times attending physicians in the ALG group took over the blocks from residents was significantly greater than that of the USG group (p=0.006) and more local anesthetic was used in the USG group (p=0.04).Conclusion: This study compared the ALG approach with the USG approach for patients undergoing mastectomy for breast cancer. Based on our observations, an attending physician is more likely to take over an ALG injection, and more local anesthetic is administered during USG single injection. Keywords: thoracic paravertebral block, regional anesthesia, mastectomy, breast cancer

This is a retrospective review of surgical management for primary lymphedema. Data were extracted from 55 articles from PubMed MEDLINE, Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials between the database inception and December 2022 to evaluate the outcomes of lymphaticovenous anastomosis (LVA) and vascularized lymph node transfer (VLNT), and outcomes of soft tissue extirpative procedures such as suction-assisted lipectomy (SAL) and extensive soft tissue excision. Data from 485 patients were compiled; these were treated with LVA ( n  = 177), VLNT ( n  = 82), SAL ( n  = 102), and excisional procedures ( n  = 124). Improvement of the lower extremity lymphedema index, the quality of life (QoL), and lymphedema symptoms were reported in most studies. LVA and VLNT led to symptomatic relief and improved QoL, reaching up to 90 and 61% average circumference reduction, respectively. Cellulitis reduction was reported in 25 and 40% of LVA and VLNT papers, respectively. The extirpative procedures, used mainly in patients with advanced disease, also led to clinical improvement from the volume reduction, as well as reduced incidence of cellulitis, although with poor cosmetic results; 87.5% of these reports recommended postoperative compression garments. The overall complication rates were 1% for LVA, 13% for VLNT, 11% for SAL, and 46% for extirpative procedures. Altogether, only one paper lacked some kind of improvement. Primary lymphedema is amenable to surgical treatment; the currently performed procedures have effectively improved symptoms and QoL in this population. Complication rates are related to the invasiveness of the chosen procedure., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Limited comparability between study groups can generate significant selection and observer bias when evaluating the efficacy of the SPY system and fluorescence imaging for implant-based breast reconstruction. In this study, the authors compared the surgical outcomes and complications during the first stage of reconstruction between reconstructions evaluated intraoperatively with fluorescence imaging using the SPY system and clinical assessment using a matched analysis., Methods: The authors conducted a retrospective review of patients undergoing total mastectomy and immediate two-stage implant-based breast reconstruction with TEs from January of 2011 to December of 2020. The rate of complication, time for TE-to-implant exchange, and time to start radiotherapy were compared between groups (intraoperative fluorescence imaging versus clinical assessment) using a propensity score-matched analysis., Results: After propensity score matching, 198 reconstructions were evaluated. There were 99 reconstructions in each group. The median time for TE-to-implant exchange (140 days versus 185 days; P = 0.476) and time to initiate adjuvant radiotherapy (144 days versus 98 days; P = 0.199) were comparable between groups. The 30-day rate of wound-related complications (21% versus 9%; P = 0.017) and 30-day rate of wound-related unplanned interventions were significantly higher in reconstructions evaluated with clinical assessment when compared with the SPY system (16% versus 5%; P = 0.011). A higher 30-day rate of seroma (19% versus 14%; P = 0.041) and hematoma (8% versus 0%; P = 0.004) were found in reconstructions assessed intraoperatively with the SPY system., Conclusions: After matching, reconstructions evaluated with fluorescence imaging exhibited a lower incidence of early wound-related complications when compared with clinical evaluation alone. Nonetheless, the Wise pattern for mastectomy was found to be the only independent predictor associated with early wound-related complications., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: Reports evaluating plastic surgeons' practices indicate there are conflicting trends regarding the use of one or two drains for implant-based breast reconstruction (IBBR). Our study aimed to perform a matched cohort analysis to examine the postoperative outcomes and complications of immediate IBBR with tissue expander (TE) using two drains versus a single drain., Methods: A propensity score-matched analysis (nearest neighbor, 1:1 matching) of immediate reconstructions using two versus one drain was conducted. Female patients undergoing immediate two-stage IBBR with TEs between January 2011 and May 2021 were included. The covariables were as follows: BMI, mastectomy weight, lymph node surgery, TE surface, plane of reconstruction, use of acellular dermal matrix products, fluorescence imaging use, and intraoperative TE volume., Results: After matching using propensity scores, 192 reconstructions were included in the final analysis: 96 in each group. The rate of 30-day complications and overall complications during the first phase of IBBR were comparable between groups. The time for drain removal, time to initiate and finalize expansions, and time for TE-to-implant exchange were comparable between groups. Diabetes (OR 3.74, p = 0.025) and an increased estimated blood loss (OR 1.004, p = 0.01) were the only independent predictors for seroma formation., Conclusion: In this matched cohort analysis evaluating the role of one versus two drains for two-stage IBBR, we found a comparable rate of complications and surgical outcomes between the two cohorts. Using two drains for immediate IBBR needs to be tailored depending on intraoperative findings., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: The Wise pattern adapted to mastectomy incisions has become a valuable asset for breast reconstruction in patients with large and ptotic breasts. The authors compared the time for exchange, time to initiate postmastectomy radiotherapy, and complication rates between Wise pattern and transverse incision pattern reconstructions., Methods: Records of patients who underwent immediate, two-stage, implant-based breast reconstruction (IBBR) between January of 2011 and December of 2020 were retrospectively reviewed. Two cohorts were compared according to the incision pattern: Wise pattern versus transverse incision pattern. Complications were compared after propensity score matching., Results: The authors initially analyzed 393 two-stage immediate IBBRs in 239 patients [91 IBBRs (23.2%) in the Wise pattern group and 302 (76.8%) in the transverse pattern group]. Expansion time (53 days versus 50 days, P = 0.9), time for tissue expander-to-implant exchange (154 versus 175 days, P = 0.547), and time to initiate postmastectomy radiotherapy (144 days versus 126 days, P = 0.616) were not different between groups. Before propensity score matching, the 30-day rate of wound-related complications (32% versus 10%, P < 0.001) and the 30-day rate of wound complications requiring excision/débridement and closure procedures (20% versus 7%, P < 0.001) were significantly higher in the Wise pattern group. After propensity score matching, the 30-day rate of wound complications was persistently higher (25% versus 10%, P = 0.03) in the Wise pattern group., Conclusions: The Wise pattern mastectomy independently increases the incidence of wound-related complications versus only transverse patterns during two-stage IBBR, even after propensity score matching. Delayed tissue expander placement may improve the safety profile of this procedure., Clinical Question/level of Evidence: Therapeutic, III., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: Implant-based breast reconstruction (IBBR) is the most common technique for breast reconstruction. The primary resource for correcting deformities, once patients have achieved an adequate volume with two-stage IBBR, is autologous fat grafting. We compared the surgical outcomes of simultaneous fat grafting during TE-to-implant exchange (SFG + TtIE) versus no fat grafting during TE-to-implant exchange (No-FGX)., Methods: A retrospective review was performed of all consecutive patients undergoing two-stage implant-based breast reconstruction with TE from January 2011 to December 2020. Propensity score matching was implemented to optimize comparability. The control group did not receive fat grafting at the time of TE-to-implant exchange., Results: After propensity score matching, 196 reconstructions were evaluated, 98 in each group. Reconstructions in the SFG + TtIE received larger implants during exchange in comparison with the No-FGX group (539 ± 135.1-cc versus 495.97 ± 148-cc, p=0.035). The mean volume of fat lipoinjected during TE-to-implant exchange in the SFG + TtIE group was 88.79 ± 41-ml. A higher proportion of reconstructions in the SFG + TtIE group underwent additional fat grafting after exchange versus the No-FGX group (19% versus 9%, p = 0.041). After propensity score matching, only the rate of fat necrosis after exchange was significantly higher in the SFG + TtIE group (10% versus 2%, p = 0.017). The rate of breast cancer recurrence (3% versus 5%, p = 1.00) was comparable between the groups., Conclusion: SFG + TtIE is a safe procedure to improve the envelope of reconstructed breasts during two-stage IBBR. SFG + TtIE does not increase the rate of periprosthetic infection or wound-related complication versus no fat grafting during TE-to-implant exchange, but increases the rate of fat necrosis., Level of Evidence Iii: Therapeutic study. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: Approximately 80% of patients undergoing total mastectomy in the US opt for implant-based breast reconstruction (IBBR). A two-stage reconstruction with tissue expander (TE) remains the most common technique. Since the implementation of ADMs, a prepectoral approach has gained popularity and is becoming the standard of care. Herein, we compared the surgical and postoperative outcomes of prepectoral versus subpectoral two-stage IBBR., Methods: A retrospective chart review was performed between January 2011 and December 2020. We included female patients undergoing immediate two-stage IBBR. The primary outcomes of this study were to compare the 30-day morbidity and the overall rate of complications during the first and second stages of reconstruction, and to compare the time to initiate postmastectomy radiotherapy (PMRT). Propensity score matching was implemented., Results: After matching, 154 reconstructions were analyzed, 77 in each group. The two matched groups exhibited comparable (p > 0.05) characteristics for all analyzed demographic and intraoperative independent variables. Reconstructions in the prepectoral group had a shortened median time for drain removal (13-days vs. 15-days, p = 0.001). The intraoperative expansion volumes were higher in the prepectoral group (300 ml versus 200 ml, p = 0.025). The 30-day morbidity and first- and second-stage complication rates were not significantly different between groups. The time to start postmastectomy radiation therapy (PMRT) was not significantly different between groups (134-days versus 126.5-days, p = 0.58)., Conclusion: Prepectoral and subpectoral TE placement had comparable complication rates during the first and second stages of IBBR. Timing for TE-to-Implant exchange and initiation of PMRT were comparable between the two approaches., Competing Interests: Declaration of Competing Interest The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2022 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: Distinguishing between a breast intraductal papilloma and a papillary lesion with atypia or malignancy can be very challenging on core biopsy. There has been a long ongoing debate over whether or not it is necessary for breast papillary lesions diagnosed on core biopsies to be surgically excised, and the upgrading rate after excision varies., Method And/or Result: This study was carried out in a subspecialized academic pathology department, with well-formed criteria established among the faculty for the categorization of breast papillary lesions, with emphasis on the morphology evaluation of cellular features. A total of 320 breast core biopsies with follow-up excisions were identified. Of these, 286 cases had concordant results between the biopsy and excision, giving a concordance rate of 89.4%, with 98% concordance (143/146) in benign papilloma, 100% (111/111) in papillary carcinoma, and 51% (32/63) in papilloma with atypia. Of the upgraded cases, two were upgraded from benign to atypical, 11 from atypia to malignancy, and only one from benign to malignant. The overall average upgrading rate was 4.4% (14/320), with the critical upgrading (from benign to atypia or malignancy) rate of 0.94% (3/320). Downgrading was only identified in the group of papilloma with atypia, with 20 of 63 cases downgraded to benign papilloma on excision., Conclusion: Our study indicates that surgical excision may not be necessary for all papillary lesions after detailed evaluation of the morphology on core biopsies. Assessing the morphological features of the epithelial cells is critical for the accurate classification and clinical management of papillary lesions., (Copyright © 2021. Published by Elsevier Inc.)

Iron reduction and sulfate reduction are two of the major biogeochemical processes that occur in anoxic sediments. Microbes that catalyze these reactions are therefore some of the most abundant organisms in the subsurface, and some of the most important. Due to the variety of mechanisms that microbes employ to derive energy from these reactions, including the use of soluble electron shuttles, the dynamics between iron- and sulfate-reducing populations under changing biogeochemical conditions still elude complete characterization. Here, we amended experimental bioreactors comprised of freshwater aquifer sediment with ferric iron, sulfate, acetate, and the model electron shuttle AQDS (9,10-anthraquinone-2,6-disulfonate) and monitored both the changing redox conditions as well as changes in the microbial community over time. The addition of the electron shuttle AQDS did increase the initial rate of FeIII reduction; however, it had little effect on the composition of the microbial community. Our results show that in both AQDS- and AQDS+ systems there was an initial dominance of organisms classified as Geobacter (a genus of dissimilatory FeIII-reducing bacteria), after which sequences classified as Desulfosporosinus (a genus of dissimilatory sulfate-reducing bacteria) came to dominate both experimental systems. Furthermore, most of the ferric iron reduction occurred under this later, ostensibly "sulfate-reducing" phase of the experiment. This calls into question the usefulness of classifying subsurface sediments by the dominant microbial process alone because of their interrelated biogeochemical consequences. To better inform models of microbially-catalyzed subsurface processes, such interactions must be more thoroughly understood under a broad range of conditions., Competing Interests: The authors have declared that no competing interests exist.

Propofol is a widely used general anesthetic, which acts by binding to and modulating several neuronal ion channels. We describe the synthesis of photoactivatable propofol analogs functionalized with an alkyne handle for bioorthogonal chemistry. Such tools are useful for detecting and isolating photolabeled proteins. We designed expedient and flexible synthetic routes to three new diazirine-based crosslinkable propofol derivatives, two of which have alkyne handles. As a proof of principle, we show that these compounds activate heterologously expressed Transient Receptor Potential Ankyrin 1 (TRPA1), a key ion channel of the pain pathway, with a similar potency as propofol in fluorescence-based functional assays. This work demonstrates that installation of the crosslinkable and clickable group on a short nonpolar spacer at the para position of propofol does not affect TRPA1 activation, supporting the utility of these chemical tools in identifying and characterizing potentially druggable binding sites in propofol-interacting proteins., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to identify predictors of mortality and potentially modifiable factors related to arrhythmias in patients that undergo transcatheter aortic valve replacement (TAVR). Patients that undergo TAVR are at risk for complete heart block requiring pacemaker implant. Additionally, other arrhythmias, specifically atrial fibrillation (AF), are common in this population. It is unclear how arrhythmias and their management contribute to mortality risk., Methods: The study analyzed 176 patients who underwent TAVR at a single center. Factors associated with pacemaker implantation within 30 days were analyzed by logistic regression. Factors associated with mortality were analyzed by Kaplan-Meier and Cox regression analyses., Results: Mean age was 80 ± 8.5 years. AF was present in 69 patients, and 39 received anticoagulation. Post-TAVR, a pacemaker was implanted in 25 patients within 30 days. Over a follow up of 566 ± 496 days, 49 patients died. In multivariable analysis, right bundle branch block remained significant (odds ratio 4.212, P = 0.012) for pacemaker implant within 30 days. The AF (hazard ratio [HR] 3.905, P = 0.001), albumin level (HR 0.316, P = 0.034), and diabetes (HR 2.323, P = 0.027) were predictors of death in a multivariate analysis, while pacemaker implant within 30 days was not. Patients with AF who were anticoagulated had improved survival in a stratified Kaplan-Meier analysis compared with those who were not anticoagulated (P = 0.0001)., Conclusion: AF, diabetes, and low albumin levels are independently associated with mortality after TAVR. In particular, patients with AF who are not anticoagulated are at highest risk for death. Efforts to identify AF and consider anticoagulation should be emphasized., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We present here the draft genome sequence of a pyridine-degrading bacterium, Micrococcus luteus ATCC 49442, which was reclassified as Pseudarthrobacter sp. strain ATCC 49442 based on its draft genome sequence. Its genome length is 4.98 Mbp, with 64.81% GC content., (Copyright © 2020 Gupta et al.)

Here, we report the draft genome sequence of Arthrobacter sp. strain ATCC 49987, consisting of three contigs with a total length of 4.4 Mbp. Based on the genome sequence, we suggest reclassification of Arthrobacter sp. strain ATCC 49987 as Pseudarthrobacter sp. strain ATCC 49987., (Copyright © 2020 Gupta et al.)

We report here the 4.9-Mb genome sequence of a quinoline-degrading bacterium, Rhodococcus sp. strain ATCC 49988. The draft genome data will enable the identification of genes and future genetic modification to enhance traits relevant to heteroaromatic compound degradation., (Copyright © 2019 Gupta et al.)

We present here the draft genome sequence of a carbazole-degrading Enterobacter species. The draft genome sequence will provide insight into various genes involved in the degradation of carbazole and other related aromatic compounds., (Copyright © 2019 Gupta et al.)

In addition to inducing anesthesia, propofol activates a key component of the pain pathway, the transient receptor potential ankyrin 1 ion channel (TRPA1). Recent mutagenesis studies suggested a potential activation site within the transmembrane domain, near the A-967079 cavity. However, mutagenesis cannot distinguish between protein-based and ligand-based mechanisms, nor can this site explain the complex modulation by propofol. Thus more direct approaches are required to reveal potentially druggable binding sites. Here we apply photoaffinity labeling using a propofol derivative, meta-azipropofol, for direct identification of binding sites in mouse TRPA1. We confirm that meta-azipropofol activates TRPA1 like the parent anesthetic, and identify two photolabeled residues (V954 and E969) in the S6 helix. In combination with docking to closed and open state models of TRPA1, photoaffinity labeling suggested that the A-967079 cavity is a positive modulatory site for propofol. Further, the photoaffinity labeling of E969 indicated pore block as a likely mechanism for propofol inhibition at high concentrations. The direct identification of drug-binding sites clarifies the molecular mechanisms of important TRPA1 agonists, and will facilitate drug design efforts to modulate TRPA1., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Studies of behavioral momentum reveal that reinforcing an alternative response in the presence of a target response reduces the rate of target responding but increases its persistence, relative to training the target response on its own. Because of the parallels between these studies and differential-reinforcement techniques to reduce problem behavior in clinical settings, alternative techniques to reduce problem behavior without enhancing its persistence are being explored. One potential solution is to train an alternative response in a separate stimulus context from problem behavior before combining the alternative stimulus with the target stimulus. The present study assessed how differences in reinforcement contingencies and rate for alternative responding influenced resistance to extinction of target responding when combining alternative and target stimuli in pigeons. Across three experiments, alternative stimuli signaling a response-reinforcer dependency and greater reinforcer rates more effectively decreased the persistence of target responding when combining alternative and target stimuli within the same extinction tests, but not when compared across separate extinction tests. Overall, these findings reveal that differences in competition between alternative and target responding produced by contingencies of alternative reinforcement could influence the effectiveness of treating problem behavior through combining stimulus contexts., (© 2016 Society for the Experimental Analysis of Behavior.)

Oncotype DX (Genomic Health, Redwood City, CA, USA, current list price $4,350.00) is a multigene quantitative reverse transcription-polymerase chain reaction-based assay that estimates the risk of distant recurrence and predicts chemotherapy benefit for patients with estrogen receptor (ER)-positive breast cancers. Studies have suggested that standard histologic variables can provide similar information. Klein and Dabbs et al have shown that Oncotype DX recurrence scores can be estimated by incorporating standard histologic variables into equations (Magee equations). Using a simple modification of the Magee equation, we predict the Oncotype DX recurrence score in an independent set of 283 cases. The Pearson correlation coefficient (r) for the Oncotype DX and average modified Magee recurrence scores was 0.6644 (n=283; P<0.0001). 100% of cases with an average modified Magee recurrence score>30 (n=8) or an average modified Magee recurrence score<9 (with an available Ki-67, n=5) would have been correctly predicted to have a high or low Oncotype DX recurrence score, respectively. 86% (38/44) of cases with an average modified Magee recurrence score≤12, and 89% (34/38) of low grade tumors (NS<6) with an ER and PR≥150, and a Ki-67<10%, would have been correctly predicted to have a low Oncotype DX recurrence score. Using an algorithmic approach to eliminate high and low risk cases, between 5% and 23% of cases would potentially not have been sent by our institution for Oncotype DX testing, creating a potential cost savings between $56,550.00 and $282,750.00. The modified Magee recurrence score along with histologic criteria may be a cost-effective alternative to the Oncotype DX in risk stratifying certain breast cancer patients. The information needed is already generated by many pathology laboratories during the initial assessment of primary breast cancer, and the equations are free.

Objectives: In this prospective pilot study, the feasibility of non-contrast dedicated breast computed tomography (bCT) to determine primary tumor volume and monitor its changes during neoadjuvant chemotherapy (NAC) treatment was investigated., Materials and Methods: Eleven women who underwent NAC were imaged with a clinical prototype dedicated bCT system at three time points - pre-, mid-, and post-treatment. The study radiologist marked the boundary of the primary tumor from which the tumor volume was quantified. An automated algorithm was developed to quantify the primary tumor volume for comparison with radiologist's segmentation. The correlation between pre-treatment tumor volumes from bCT and MRI, and the correlation and concordance in tumor size between post-treatment bCT and pathology were determined., Results: Tumor volumes from automated and radiologist's segmentations were correlated (Pearson's r = 0.935, P < 0.001) and were not different over all time points [P = 0.808, repeated measures analysis of variance (ANOVA)]. Pre-treatment tumor volumes from MRI and bCT were correlated (r = 0.905, P < 0.001). Tumor size from post-treatment bCT was correlated with pathology (r = 0.987, P = 0.002) for invasive ductal carcinoma larger than 5 mm and the maximum difference in tumor size was 0.57 cm. The presence of biopsy clip (3 mm) limited the ability to accurately measure tumors smaller than 5 mm. All study participants were pathologically assessed to be responders, with three subjects experiencing complete pathologic response for invasive cancer and the reminder experiencing partial response. Compared to pre-treatment tumor volume, there was a statistically significant (P = 0.0003, paired t-test) reduction in tumor volume at mid-treatment observed with bCT, with an average tumor volume reduction of 47%., Conclusions: This pilot study suggests that dedicated non-contrast bCT has the potential to serve as an expedient imaging tool for monitoring tumor volume changes during NAC. Larger studies are needed in future.

Aims: Historically, nuclear staining of ≥10% of invasive tumour cells has been used for oestrogen receptor (ER) positivity. In 2010, ASCO/CAP guidelines recommended the cut-off value be changed to nuclear staining of ≥1%. This study will analyse the relationships between levels of ER expression and clinicopathological features and clinical outcomes, with an emphasis on the ER 1-10% subgroup., Methods and Results: We analysed clinicopathological features in five subgroups based on ER expression levels in 1700 consecutive invasive breast cancer patients diagnosed and treated at our institution between 2000 and 2011. Of the cases, 24% had ER expression <1%, 2% were ER 1-10%, 5% were 11-50%, 5% were 51-70% and 64% were 71-100%. We observed four subgroups of patient cohorts (ER <1%, 1-10%, 11-70% and 71-100%) that were unique in Nottingham grade, nuclear grade, progesterone receptor expression and disease-free survival. Of the 341 patients with follow-up data, we found no significant differences in pathological features between patients in the ER 11-50% and ER 51-70% subgroups., Conclusion: These data support the important role of ER in breast cancer, and the importance of accurate testing and quantitative reporting for ER. Tumours with ER 1-10% are not common, and further studies are needed to understand more clearly this subgroup of breast cancer., (© 2014 John Wiley & Sons Ltd.)

Netto shinju, or Internet group suicide, is a contemporary form of Japanese suicide where strangers connect on the Internet and make plans to commit suicide together. In the past decade, numerous incidents have occurred whereby young Japanese make contact on the Internet, exchange tips on suicide methods, and make plans to meet offline for group/individual suicide. A systematic qualitative content/thematic analysis of online communications posted on a popular Japanese suicide bulletin board yielded a textured, thematic understanding of this phenomenon. Themes identified reflected Shneidman's theory of suicide but with an emphasis on interpersonal concerns that are embedded in Japanese culture.

Background: Studies show that women with low vitamin D levels have an increased risk of breast cancer (BC) incidence and mortality, but there is a lack of research examining vitamin D levels and prognostic variables in BC patients. The aim of this study is to examine 25-OH vitamin D levels between BC cases and controls and by prognostic indicators among BC cases., Methods: 25-OH vitamin D levels were collected from 194 women who underwent BC surgery and 194 cancer-free (CF) controls at the University of Rochester between January 2009 and October 2010. Mean 25-OH vitamin D levels and odds ratios (OR) were calculated by case/control status for the overall cohort and by prognostic indicators (invasiveness, ER status, triple-negative status, Oncotype DX score, molecular phenotype) for BC cases., Results: BC cases had significantly lower 25-OH vitamin D levels than CF controls (BC: 32.7 ng/mL vs. CF: 37.4 ng/mL; P = .02). In case-series analyses, women with suboptimal 25-OH vitamin D concentrations (<32 ng/mL) had significantly higher odds of having ER- (OR = 2.59, 95% confidence interval [95% CI] = 1.08-6.23) and triple-negative cancer (OR = 3.15, 95% CI = 1.05-9.49) than those with optimal 25-OH D concentrations. Women with basal-like phenotype had lower 25-OH vitamin D levels than women luminal A phenotype (basal-like: 24.2 ng/mL vs. luminal A: 32.8 ng/mL; P = 0.04)., Conclusions: BC patients with a more aggressive molecular phenotype (basal-like) and worse prognostic indicators (ER- and triple-negative) had lower mean 25-OH vitamin D levels. Further research is needed to elucidate the biological relationship between vitamin D and BC progression.

Background: Breast-conserving therapy (BCT) is an accepted therapeutic option for most breast cancer patients. However, mastectomy is still performed in 30-50% of patients undergoing surgeries. There is increasing interest in preservation of the nipple and/or areola in hopes of achieving improved cosmetic and functional outcomes; however, the oncologic safety of nipple-areolar complex (NAC) preservation is a major concern. We sought to identify the predictive factors for NAC involvement in breast cancer patients., Methods: We analyzed the rates and types of NAC involvement by breast carcinoma, and its association with other clinicopathologic features of the tumors in 787 consecutive therapeutic mastectomies performed at our institution between 1997 and 2009., Results: Among these, 75 cases (9.5%) demonstrated NAC involvement. Only 21 (28%) of 75 of cases with NAC involvement could be identified grossly by inspection of the surgical specimen (seven of these had been clinically identified). NAC involvement was most significantly associated with tumors located in all four quadrants (P<0.0001), tumors>5 cm in size (P=0.0014 for invasive carcinoma and P=0.0032 for in-situ carcinoma), grade 3 tumors (P=0.0192), tumors with higher nuclear grades (P=0.0184), and tumors with HER2 overexpression (P=0.0137)., Conclusions: On the basis of our findings, we have developed a mathematical model that is based on the extent and location of the tumor, HER2 expression, and nuclear grade that predicts the probability of NAC involvement by breast cancer. This model may aid in preoperative planning in selecting appropriate surgical procedures based on an individual patient's relative risk of NAC involvement.

Tumor cells release several factors that can help the progression of the tumor by directly supporting tumor growth and/or suppressing host antitumor immunity. Here, we report that human primary breast tumor cells not only express elevated levels of heat shock protein 27 (Hsp27) at the intracellular level but also release extremely high levels of Hsp27 compared with the same patients' serum Hsp27 levels, predicting an acutely increased concentration of soluble Hsp27 in the human breast tumor microenvironment (HBTM). We demonstrate that Hsp27 levels in the HBTM can be extremely elevated as evidenced by high soluble Hsp27 levels in patients' tumor interstitial fluid. Because increasing numbers of tumor-associated macrophages (TAM) in the HBTM negatively correlate to patients' clinical outcomes and we have previously reported the immunoregulatory activity of soluble Hsp27, here, we tested for any specific effects of soluble Hsp27 on human monocyte to macrophage differentiation. We demonstrate that soluble Hsp27 causes the differentiation of monocytes to macrophages with immuno-tolerizing phenotypes (HLA-DRlow, CD86low, PD-L1high, ILT2high, and ILT4high). We detected the presence of TAMs with similar phenotypes in breast cancer patients. Hsp27-differentiated macrophages induce severe unresponsiveness/anergy in T cells. Moreover, these macrophages lose tumoricidal activity but become extremely proangiogenic, inducing significant neovascularization, a process that is critically important for tumor growth. Thus, our data demonstrate a novel immune escape and tumor growth-supporting mechanism mediated by soluble Hsp27 that may be operative in human breast cancer., (© 2011 AACR.)

Among the 77 infiltrating breast carcinomas, we found that progesterone receptor (PR) expression was inversely associated with recurrence score (RS, p < .0001). RS is also significantly associated with tubule formation, mitosis, and luminal B subtype. The equation of RS = 17.489 + 2.071 (tubal formation) + 2.926 (mitosis) -2.408 (PR) -1.061 (HER2) + 7.051 (luminal A) + 29.172 (luminal B) predicts RS with an R² of 0.65. In conclusion, PR negativity, luminal B subtype, tubal formation, and mitosis are strongly correlated with a higher RS.

Gene expression profiling with breast carcinomas has allowed further classification of these tumors into 5 distinct subtypes (luminal A, luminal B, HER2-overexpression, basal-like, and normal-like) with unique clinical outcomes. Subsequent studies have shown that breast carcinomas can also be divided into 5 similar subgroups using immunohistochemical (IHC) analysis with a limited panel of molecular markers (including estrogen receptor, progesterone receptor, HER2, CK5/6, and epidermal growth factor receptor). These subgroups have distinguishing features closely associated with subtypes defined by gene expression profiling, including distinct clinical outcomes. This review aims to present the current data on molecular classification for breast carcinoma, and its clinical significance, with an emphasis on IHC-based studies and the pros and cons of these molecular classifications. We also propose a standardized IHC-based molecular classification, in the hope that it will promote more uniform large multicenter studies, and facilitate its clinical application.

Background: Despite the National Institutes of Health consensus statement in 1991 that breast-conserving surgery (BCS) followed by radiotherapy is an appropriate approach to the treatment of early-stage breast carcinoma, studies have shown a relatively low rate of BCS in the United States. The current study investigated predictors of breast conservation therapy in a large, diverse patient population., Methods: Between 1990 and 1998, 43,111 patients underwent surgery for breast carcinoma and were entered into the Cancer Surveillance Program database for Los Angeles County. Of these, 29,666 (68.3%) had complete data on patient demographics, staging, surgeon, type of surgery, and hospital. Data were collected regarding extent of disease, lymph node status, tumor size, age, race, socioeconomic status (SES), surgeon specialization, surgeon volume, hospital specialization, and hospital volume. Univariate and multivariate analyses were performed., Results: Univariate analysis showed that extent of disease, lymph node status, tumor size, age, race, SES, surgeon and hospital specialization, and surgeon and hospital volume all were significantly associated with surgery type (P <0.0001). Multivariate analysis showed that not only did extent of disease impact choice of surgery, but so did race, SES, hospital volume, surgeon volume, and surgeon specialization (P <0.0001)., Conclusions: These results suggest that not only does the extent of locoregional disease play a role in the likelihood of a woman undergoing breast conservation therapy, but patient age, socioeconomic status, racial/ethnic factors, and the experience of both the surgeon and hospital have an effect., (2005 American Cancer Society.)

Bacterial contamination is an ongoing problem for commercial fuel ethanol production facilities. Both chronic and acute infections are of concern, due to the fact that bacteria compete with the ethanol-producing yeast for sugar substrates and micronutrients. Lactic acid levels often rise during bouts of contamination, suggesting that the most common contaminants are lactic acid bacteria. However, quantitative surveys of commercial corn-based fuel ethanol facilities are lacking. For this study, samples were collected from one wet mill and two dry grind fuel ethanol facilities over a 9 month period at strategic time points and locations along the production lines, and bacterial contaminants were isolated and identified. Contamination in the wet mill facility consistently reached 10(6) bacteria/ml. Titers from dry grind facilities were more variable but often reached 10(8)/ml. Antibiotics were not used in the wet mill operation. One dry grind facility added antibiotic to the yeast propagation tank only, while the second facility dosed the fermentation with antibiotic every 4 h. Neither dosing procedure appeared to reliably reduce overall contamination, although the second facility showed less diversity among contaminants. Lactobacillus species were the most abundant isolates from all three plants, averaging 51, 38, and 77% of total isolates from the wet mill and the first and second dry grind facilities, respectively. Although populations varied over time, individual facilities tended to exhibit characteristic bacterial profiles, suggesting the occurrence of persistent endemic infections.

To compare the effect of hyperthermia on maximal oxygen uptake (VO2max) in men and women, VO2max was measured in 11 male and 11 female runners under seven conditions involving various ambient temperatures (Ta at 50% RH) and preheating designed to manipulate the esophageal (Tes) and mean skin (Tsk) temperatures at VO2max. The conditions were: 25 degrees C, no preheating (control); 25, 35, 40, and 45 degrees C, with exercise-induced preheating by a 20-min walk at approximately 33% of control VO2max; 45 degrees C, no preheating; and 45 degrees C, with passive preheating during which Tes and Tsk were increased to the same degree as at the end of the 20-min walk at 45 degrees C. Compared to VO2max (l x min(-1)) in the control condition (4.52+/-0.46 in men, 3.01+/-0.45 in women), VO2max in men and women was reduced with exercise-induced or passive preheating and increased Ta, approximately 4% at 35 degrees C, approximately 9% at 40 degrees C and approximately 18% at 45 degrees C. Percentage reductions (7-36%) in physical performance (treadmill test time to exhaustion) were strongly related to reductions in VO2max (r=0.82-0.84). The effects of hyperthermia on VO2max and physical performance in men and women were almost identical. We conclude that men and women do not differ in their thermal responses to maximal exercise, or in the relationship of hyperthermia to reductions in VO2max and physical performance at high temperature. Data are reported as mean (SD) unless otherwise stated.

The MammoSite Radiation Therapy System (RTS) has become the most widely used brachytherapy method used in the treatment of breast cancer, due to its ease of use, short learning curve, and requirement of only one interstitial path through the breast skin. The dosimetry is simple, one source position in the middle of the MammoSite balloon catheter. The data on long-term complications, however are not available, though developing. Trials for DCIS are being developed, as well as a comparison trial to standard external beam radiation as well as other forms of accelerated partial breast irradiation (APBI).

Background: Many believe that breast cancer should be treated by specialists. We studied the effect of surgeon and hospital specialization on survival after breast cancer treatment in a large, well-defined patient population., Methods: The Cancer Surveillance Program database for Los Angeles County was reviewed. Between 1990 and 1998, 43,411 cases of breast cancer were diagnosed, of which 29,666 had complete data on surgeon, hospital, and staging information. Patients were stratified on the basis of surgeon and hospital specialization, as well as by age, race, stage, surgical procedure, and surgeon and hospital case volume. An analysis of survival and its dependence on these factors was performed., Results: Age, race, socioeconomic status, tumor size, nodal status, extent of disease, surgeon specialization, surgeon case volume, and hospital case volume were all associated with 5-year survival after diagnosis of breast cancer. Treatment at a specialty center did not affect survival. Multivariate analysis indicated that type of surgeon was an independent predictor of survival (relative risk,.77), as were both hospital and surgeon case volume., Conclusions: Treatment by a surgical oncologist resulted in a 33% reduction in the risk of death at 5 years. The effect of surgical specialization cannot be entirely attributed to volume effects.

We tested the hypothesis that elevation in heart rate (HR) during submaximal exercise in the heat is related, in part, to increased percentage of maximal O(2) uptake (%Vo(2 max)) utilized due to reduced maximal O(2) uptake (Vo(2 max)) measured after exercise under the same thermal conditions. Peak O(2) uptake (Vo(2 peak)), O(2) uptake, and HR during submaximal exercise were measured in 22 male and female runners under four environmental conditions designed to manipulate HR during submaximal exercise and Vo(2 peak). The conditions involved walking for 20 min at approximately 33% of control Vo(2 max) in 25, 35, 40, and 45 degrees C followed immediately by measurement of Vo(2 peak) in the same thermal environment. Vo(2 peak) decreased progressively (3.77 +/- 0.19, 3.61 +/- 0.18, 3.44 +/- 0.17, and 3.13 +/- 0.16 l/min) and HR at the end of the submaximal exercise increased progressively (107 +/- 2, 112 +/- 2, 120 +/- 2, and 137 +/- 2 beats/min) with increasing ambient temperature (T(a)). HR and %Vo(2 peak) increased in an identical fashion with increasing T(a). We conclude that elevation in HR during submaximal exercise in the heat is related, in part, to the increase in %Vo(2 peak) utilized, which is caused by reduced Vo(2 peak) measured during exercise in the heat. At high T(a), the dissociation of HR from %Vo(2 peak) measured after sustained submaximal exercise is less than if Vo(2 max) is assumed to be unchanged during exercise in the heat.

Purpose: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy., Patients and Methods: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan., Results: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer)., Conclusion: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.

The iron chelator deferoxamine has been reported to inhibit both xanthine oxidase (XO) and xanthine dehydrogenase activity, but the relationship of this effect to the availability of iron in the cellular and tissue environment remains unexplored. XO and total xanthine oxidoreductase activity in cultured V79 cells was increased with exposure to ferric ammonium sulfate and inhibited by deferoxamine. Lung XO and total xanthine oxidoreductase activities were reduced in rats fed an iron-depleted diet and increased in rats supplemented with iron, without change in the ratio of XO to total oxidoreductase. Intratracheal injection of an iron salt or silica-iron, but not aluminum salts or silica-zinc, significantly increased rat lung XO and total xanthine oxidoreductase activities, immunoreactive xanthine oxidoreductase, and the concentration of urate in bronchoalveolar fluid. These results suggest the possibility that the production of uric acid, a major chelator of iron in extracellular fluid, is directly influenced by iron-mediated regulation of the expression and/or activity of its enzymatic source, xanthine oxidase.

Purpose: The aim of this study was to determine the effectiveness of a focused breast skills workshop for teaching clinical skills to third-year medical students., Methodology: One hundred twenty-four third-year medical students involved in the surgical core clerkship were randomly assigned to two groups. Group 1 (n = 67) participated in a 2-h focused breast skills workshop. Group 2 (n = 57) received "traditional" ambulatory teaching for a period of 4 h in the breast clinic. The focused workshop consisted of a series of encounters concentrating on mammogram and ultrasound interpretation, physical examination skills, lump detection, and workup of a breast mass. Both groups received a didactic core curriculum lecture from surgical faculty. All students completed a satisfaction rating scale and a subset of students completed a pre- and postencounter self-efficacy rating scale on several aspects of breast skills. Student's t test was used to compare the groups in the areas of clinical skills as evidenced by performance on the breast-specific items on the end of the clerkship Objective Structure Clinical Examination and student satisfaction as evidenced by their response on a satisfaction rating scale. ANCOVA (controlling for preencounter self-efficacy rating) was used to compare the change scores between pre- and postencounter self-efficacy ratings., Results: Students in Group 1 performed significantly higher than the students in Group 2 in the areas of clinical examination skills (t = -2.99, P < 0.05); in sensitivity (t = -5.82, P < 0.05) and specificity (t = -7.27, P < 0.05) in the examination of breast models; and with their satisfaction with the encounter (t = 10.72, P < 0.05). Students in Group 1 also demonstrated a higher level of confidence in their breast skills at the end of the clerkship than students in Group 2 (F = 6.22, P < 0.05)., Conclusions: The focused breast skills workshop is more effective than the traditional ambulatory setting for teaching clinical breast examination skills. This setting also demonstrated the development of higher confidence in breast skills than the traditional ambulatory setting.

Purpose: To explore the feasibility of a short course of hypofractionated conformal radiation therapy to the tumor bed as part of a breast preservation protocol in postmenopausal patients with nonpalpable pT1N0 stage breast cancer., Materials and Methods: The tumor bed was imaged at computed tomography (CT) in the prone position on a dedicated table. The same table and position were used for treatment with a 4-MV linear accelerator. The planning target volume was the tumor bed plus a 1-2-cm margin defined at postmastectomy CT. A regimen of five fractions was tested in this pilot dose study. Cosmesis was assessed by patients and physicians before treatment and 36 months after treatment., Results: Ten consecutive patients who were eligible for the study were assigned to one of three dose-per-fraction regimens; nine were treatable with the proposed technique on the basis of CT findings. Patients received five fractions over 10 days (total dose range, 25-30 Gy): Three received 5.0 Gy per fraction; four, 5.5 Gy; and two, 6.0 Gy. At minimum follow-up of 36 months (range, 36-53 months), all patients were alive and disease free with good to excellent cosmesis., Conclusion: Hypofractionated conformal breast radiation therapy is feasible. Further studies are warranted.

Background: We examined the clinicopathologic profile of T1 cancers to determine whether palpable cancers are different from nonpalpable cancers., Methods: A prospective database was reviewed. Palpable T1 cancers were compared with nonpalpable T1 cancers. Initial significance was determined by chi2 analysis. Factors found to be significant were then reanalyzed. controlling for tumor size by logistic or linear regression, as appropriate., Results: Of 1263 T1 cancers treated between 1981 and 2000, 857 (68%) were palpable and 401 (32%) were nonpalpable. Palpability correlated with pathologic tumor size, mitotic grade, nuclear grade, high S-phase, lymphovascular invasion, nodal positivity, and lack of extensive intraductal component, multifocality, and multicentricity. There was no significant difference in estrogen receptor, progesterone receptor or Her-2/neu status, ploidy, or DNA index. Breast cancer-specific survival was worse for patients with palpable cancers., Conclusions: Palpable cancers are inherently different from nonpalpable cancers, with a less diffuse growth pattern, higher metastatic potential, higher proliferative activity, more nuclear abnormalities, and a worse prognosis.

Axillary lymph node status continues to be the single most important prognostic variable for breast cancer survival despite significant progress in the molecular and genetic characterization of breast malignancies. All patients with invasive breast cancer who underwent axillary lymph node dissection as part of their treatment were evaluated by 11 clinical and pathologic factors, including the primary lesion's T category (TNM staging system), whether the lesion was clinically palpable, the presence of lymphatic or vascular invasion, nuclear grade, estrogen and progesterone receptors, S-phase, age, HER2/neu overexpression, histology (infiltrating lobular or ductal), and ploidy. A total of 2282 axillary dissections were performed: 391 in patients with ductal carcinoma in situ (DCIS) [3 of which (0.8%) contained metastases] and 1891 in patients with invasive breast cancer [680 of which (36%) contained metastases]. Multivariate analysis of patients with invasive cancer identified four factors as independent predictors of axillary lymph node metastases: lymph/vascular invasion, tumor size, nuclear grade, tumor palpability. Among a group of 189 patients with nonpalpable, non-high-grade invasive lesions 15 mm or smaller without lymph/vascular invasion, only 6 (3%) had metastases to lymph nodes. If any three of the favorable factors were present, lymph node positivity was 6% or less. Clinical and pathologic feature of the primary lesions can be used to estimate the risk of axillary lymph node metastases. Such risk assessment can be used for the treatment decision-making process.

Esophageal adenocarcinoma (EAC) arises after normal squamous mucosa undergoes metaplasia to specialized columnar epithelium (intestinal metaplasia or Barrett's esophagus), which can then ultimately progress to dysplasia and subsequent malignancy. Epigenetic studies of this model have thus far been limited to the DNA methylation analysis of a few genes. In this study, we analyzed a panel of 20 genes using a quantitative, high-throughput methylation assay, METHYLIGHT: We used this broader approach to gain insight into concordant methylation behavior between genes and to generate epigenomic fingerprints for the different histological stages of EAC. Our study included a total of 104 tissue specimens from 51 patients with different stages of Barrett's esophagus and/or associated adenocarcinoma. We screened 84 of these samples with the full panel of 20 genes and found distinct classes of methylation patterns in the different types of tissue. The most informative genes were those with an intermediate frequency of significant hypermethylation [ranging from 15% (CDKN2A) to 60% (MGMT) of the samples]. This group could be further subdivided into three classes, according to the absence (CDKN2A, ESR1, and MYOD1) or presence (CALCA, MGMT, and TIMP3) of methylation in normal esophageal mucosa and stomach, or the infrequent methylation of normal esophageal mucosa accompanied by methylation in all normal stomach samples (APC). The other genes were less informative, because the frequency of hypermethylation was below 5% (ARF, CDH1, CDKN2B, GSTP1, MLH1, PTGS2, and THBS1), completely absent (CTNNB1, RB1, TGFBR2, and TYMS1), or ubiquitous (HIC1 and MTHFR), regardless of tissue type. Each class undergoes unique epigenetic changes at different steps of disease progression of EAC, suggesting a step-wise loss of multiple protective barriers against CpG island hypermethylation. The aberrant hypermethylation occurs at many different loci in the same tissues, suggestive of an overall deregulation of methylation control in EAC tumorigenesis. However, we did not find evidence for a distinct group of tumors with a CpG island methylator phenotype. Finally, we found that normal and metaplastic tissues from patients with evidence of associated dysplasia or cancer had a significantly higher incidence of hypermethylation than similar tissues from patients with no further progression of their disease. The fact that the samples from these two groups of patients were histologically indistinguishable, yet molecularly distinct, suggests that the occurrence of such hypermethylation may provide a clinical tool to identify patients with premalignant Barrett's who are at risk for further progression.

Background: It is thought that implants interfere with breast cancer diagnosis and that cancers in women who have had breast augmentation carry a worse prognosis., Methods: A prospective breast cancer database was reviewed, comparing augmented and nonaugmented patients for details of histology, palpability, tumor size, nodal status, mammographic status, receptor status, nuclear grade, stage, and outcome., Results: Ninety-nine cancers in augmented women and 2857 cancers in nonaugmented women were identified. Among these women, mammography was normal in 43% of those who had had augmentation and in 5% of those who had not. Augmented women were more likely to have palpable cancers (83% vs. 59%) and nodal involvement (48% vs. 36%), and less likely to have ductal carcinoma in situ (DCIS) (18% vs. 28%). When comparing only women younger than 50, the differences in invasiveness and nodal status lost significance. Cancers diagnosed in the 1990s were more likely to be nonpalpable and noninvasive than those diagnosed in the 1980s. This trend was more pronounced in the augmented population., Conclusions: Augmented patients were more likely to have palpable cancers, although the overall stage and outcome were similar to those of nonaugmented women. Although there have been significant improvements in our ability to diagnose early breast cancer over the past two decades, mammography continues to be suboptimal in augmented women.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group of lesions with diverse malignant potential. It is the most rapidly growing subgroup within the breast cancer family with more than 42 000 new cases diagnosed in the United States during 2000. Most new cases are nonpalpable and are discovered mammographically. Treatment is controversial and ranges from excision only, to excision with radiation therapy, to mastectomy. Prospective randomized trials reveal an approximate 50% reduction in local recurrence rate overall with the addition of radiation therapy to excisional surgery, but the published prospective data do not allow the selection of subgroups in whom the benefit from radiation therapy is so small that its risks outweigh its benefits. Nonrandomized single facility series suggest that age, family history, nuclear grade, comedo-type necrosis, tumor size and margin width are all important factors in predicting local recurrence and that one or more of these factors could be used to select subgroups of patients who do not benefit sufficiently from radiation therapy to merit its use. When all patients with ductal carcinoma in situ are considered, the overall mortality from breast cancer is extremely low, only about 1-2%. When conservative treatment fails, approximately 50% of all local recurrences are invasive breast cancer. In spite of this, the mortality rate following invasive local recurrence is relatively low, about 12% with eight years of actuarial follow-up. Genetic changes routinely precede morphological evidence of malignant transformation. Lessons learned from ongoing basic science research will help us to identify those DCIS lesions that are unlikely to progress and to prevent progression in the rest.

Two closely related enzymes with more than 50% sequence identity have been identified that catalyze the esterification of cholesterol using acyl-CoA substrates, namely acyl-CoA:cholesterol acyltransferase 1 (ACAT1) and ACAT2. Both are membrane-spanning proteins believed to reside in the endoplasmic reticulum of cells. ACAT2 has been hypothesized to be associated with lipoprotein particle secretion whereas ACAT1 is ubiquitous and may serve a more general role in cellular cholesterol homeostasis. We have prepared and affinity purified rabbit polyclonal antibodies unique to either ACAT enzyme to identify their cellular localization in liver and intestine, the two main lipoprotein-secreting tissues of the body, and for comparison, kidney and adrenal. In the liver, ACAT2 was identified in the rough endoplasmic reticulum of essentially all hepatocytes whereas ACAT1 was confined to cells lining the intercellular spaces among hepatocytes in a pattern typical of Kupffer cells. In the intestine, ACAT2 signal was strongly present in the apical third of the mucosal cells, whereas ACAT1 staining was diffuse throughout the mucosal cell, but with strong signal in goblet cells, Paneth cells, and villus macrophages. In the kidney, ACAT1 immunostaining was specific for the distal tubules and podocytes within the glomerulus. In the adrenal, ACAT1 signal was strongly present in the cells of the cortex, and absent from other adrenal cell types. No ACAT2 signal was identified in the kidney or adrenal. We conclude that only the cells of the liver and intestine that secrete apolipoprotein B-containing lipoproteins contain ACAT2, whereas ACAT1 is present in numerous other cell types. The data clearly suggest separate functions for these two closely related enzymes, with ACAT2 being most closely associated with plasma cholesterol levels.

Esophageal adenocarcinoma (EAC) is thought to develop through a multistage process in which Barrett's metaplasia progresses through low- and high-grade dysplasia to invasive cancer. Transcriptional silencing of tumor suppressor genes by promoter CpG island hypermethylation has been observed in many types of human cancer. Analysis of CpG island hypermethylation in EAC has thus far been limited to the CDKN2A (p16) gene. In this study, we extend the methylation analysis of EAC to include three other genes, APC, CDH1 (E-cadherin), and ESR1 (ER, estrogen receptor alpha), in addition to CDKN2A. Molecular analysis can provide insight into the complex relationships between tissues with different histologies in Barrett's esophagus and associated adenocarcinoma. Therefore, we have mapped the spatial distribution of methylation patterns in six esophagectomy cases in detail. Hypermethylation of the four CpG islands was analyzed by the MethyLight technique in 107 biopsies derived from these six patients for a total of 428 methylation analyses. Our results show that normal esophageal squamous epithelium is unmethylated at all four CpG islands. CDH1 is unmethylated in most other tissue types as well. Hypermethylation of ESR1 is seen at high frequency in inflammatory reflux esophagitis and at all subsequent stages, whereas APC and CDKN2A hypermethylation is found in Barrett's metaplasia, dysplasia, and EAC. When it occurs, hypermethylation of APC, CDKN2A, and ESR1 is usually found in a large contiguous field, suggesting either a concerted methylation change associated with metaplasia or a clonal expansion of cells with abnormal hypermethylation.

Barrett's esophagus is a multistage polyclonal disease that is associated with the development of adenocarcinoma of the esophagus and esophagogastric junction. Telomerase activation is associated with cellular immortality and carcinogenesis, and increased expression of the telomerase reverse transcriptase catalytic subunit (hTERT) has been used for the early detection of malignant diseases. To identify biomarkers associated with each stage of the Barrett's process, relative mRNA expression levels of hTERT were measured using a quantitative reverse transcription-polymerase chain reaction method (ABI 7700 Sequence Detector (TaqMan system) in Barrett's intestinal metaplasia (n = 14), Barrett's dysplasia (n = 10), Barrett's adenocarcinoma (n = 14), and matching normal squamous esophagus tissues (n = 32). hTERT expression was significantly increased at all stages of Barrett's esophagus, including the intestinal metaplasia stage, compared to normal tissues from patients without cancer (intestinal metaplasia vs. normal esophagus, P <0.0001; dysplasia, P = 0.001; adenocarcinoma, P = 0.007; all Mann-Whitney U test ). hTERT expression levels were significantly higher in adenocarcinoma tissues than in intestinal metaplasia tissues (P = 0.003), and were higher in dysplasia compared with intestinal metaplasia tissues (P = 0.056). hTERT levels were also significantly higher in histologically normal squamous esophagus tissues from cancer patients than in normal esophagus tissues from patients with no cancer (P = 0.013). Very high expression levels ([hTERT x 100: beta-actin] >20) were found only in patients with cancer. These findings suggest that telomerase activation is an important early event in the development of Barrett's esophagus and esophageal adenocarcinoma, that very high telomerase levels may be a clinically useful biomarker for the detection of occult adenocarcinoma, and that a widespread cancer "field" effect is present in the esophagus of patients with Barrett's cancer.

Introduction: Approximately 15% of breast cancer patients present with large tumors that involve the skin, the chest wall, or the regional lymph nodes. Multimodality therapy is required, to provide the best chance for long-term survival. We have developed a regimen of paclitaxel, with concomitant radiation, as a primary therapy in patients with locally advanced breast cancer., Methods: Eligible patients had locally advanced breast cancer (stage IIB or III). After obtaining informed consent, patients received paclitaxel (30 mg/m2 during 1 hour) twice per week for 8 weeks and radiotherapy to 45 Gy (25 fractions, at 180 cGy/fraction, to the breast and regional nodes). Patients then underwent modified radical mastectomy followed by postoperative polychemotherapy., Results: Twenty-nine patients were enrolled. Of these, 28 were assessable for clinical response and toxicity, and 27 were assessable for pathological response. Objective clinical response was achieved in 89%. At the time of surgery, 33% had no or minimal microscopic residual disease. Chemoradiation-related acute toxicity was limited; however, surgical complications occurred in 41% of patients., Conclusions: Preoperative paclitaxel with radiotherapy is well tolerated and provides significant pathological response, in up to 33% of patients with locally advanced breast cancer, but with a significant postoperative morbidity rate.

Introduction: APC and TP53 are tumor suppressor genes known to be altered frequently in human esophageal adenocarcinoma (EAC), which arises as a complication of reflux disease. To determine the functional role of these genes in the development of EAC, we have created reflux in mice gene-targeted for either Trp53 or Apc., Methods: Wild-type (WT), p53-knockout (Trp53-/-), or Apc-mutated (ApcMin/+) mice were generated in our breeding colony. Total gastrectomy with esophagojejunostomy was performed at 6 weeks of age, creating jejunoesophageal reflux. Unoperated control mice were maintained under identical conditions. Mice were sacrificed at 30 weeks of age. Histology of the esophagus and jejunal anastamosis or gastroesophageal junction was reviewed by a single pathologist blinded to the genotype of the animal., Results: The esophagus was normal in all of the unoperated mice (6 ApcMin/+, 6 WT, and 6 Trp53-/-). All operated mice (6 ApcMin/+, 12 WT, and 4 Trp53-/-) had esophagitis, with squamous hyperplasia and early focal ulceration. Barrett's metaplasia was identified in 33% of the operated ApcMin/+ (2/6) and 25% of the Trp53-/- (1/4) mice, but not in the WT mice. Of 4 operated Trp53-/- mice, all developed severe dysplasia of the squamous epithelium and 2 (50%) had EAC on histology, although no gross tumors were seen. No severe dysplasia or carcinoma was identified in any of the ApcMin/+ or WT mice., Conclusions: Loss of either Trp53 or Apc leads to the development of columnar metaplasia, whereas loss of Trp53, but not Apc, leads to development of cancer in mice with jejunoesophageal reflux., (Copyright 1999 Academic Press.)

Peroxynitrite (ONOO-), formed by the reaction between nitric oxide (. NO) and superoxide, has been implicated in the etiology of numerous disease processes. Low molecular weight antioxidants, including uric acid, may minimize ONOO---mediated damage to tissues. The tissue-sparing effects of uric acid are typically attributed to oxidant scavenging; however, little attention has been paid to the biology of the reaction products. In this study, a previously unidentified uric acid derivative was detected in ONOO--treated human plasma. The product of the uric acid/ONOO- reaction resulted in endothelium-independent vasorelaxation of rat thoracic aorta, with an EC50 value in the range of 0.03-0.3 microM. Oxyhemoglobin, a .NO scavenger, completely attenuated detectable .NO release and vascular relaxation. Uric acid plus decomposed ONOO- neither released .NO nor altered vascular reactivity. Electrochemical quantification of .NO confirmed that the uric acid/ONOO- reaction resulted in spontaneous (thiol-independent) and protracted (t1/2 approximately 125 min) release of .NO. Mass spectroscopic analysis indicated that the product was a nitrated uric acid derivative. The uric acid nitration/nitrosation product may play a pivotal role in human pathophysiology by releasing .NO, which could decrease vascular tone, increase tissue blood flow, and thereby constitute a role for uric acid not previously described.